Mammalian prostatic and lysosomal acid phosphatases (EC 3.1.3.2.) include a covalent phosphohistidine intermediate in their reaction mechanism, and they are thus called histidine acid phosphatases. The same histidine acid phosphatase group includes E. coli pH 2.5 acid phosphatase and glucose-1-phosphatase, yeast acid phosphatases, Aspergillus phytases A and B, and E. coli phytase. E. coli phytase catalyzes the sequential hydrolysis of phosphate phytate (myo-inositol-1,2,3,4,5,6-hexakisphosphate, IP6) to less phosphorylated myo-inositol derivatives and inorganic phosphate. IP6 and its derivatives have functions in RNA export, DNA repair, and DNA recombination and in endocytosis and vesicular trafficking.
The inventor's earlier structural studies of PAP showed that the α/β domain resembles the structure of phosphoglycerate mutase. This domain contains a sequence motif that is also present in the bifunctional phosphofructokinase/fructose bisphosphatase. The active site of PAP is a rather open, readily accessible cleft. Despite low sequence homology (14% identity), the crystal structure of E. coli phytase is closely related to PAP. The histidine residue in the conserved motif, RHGXRXP, serves as a nucleophile in the formation of a covalent phosphohistidine intermediate, and the aspartatic acid residue of the C-terminal conserved histidine domain motif serves as a proton donor to the oxygen atom of the phosphoester bond.
There are two forms of PAP, intracellular and secreted. The physiological substrate of hPAP has been unclear. It has been suggested that the growth-suppressing effect of hPAP is due to its intrinsic protein tyrosine phosphatase activity, and this suggestion was supported by theoretical modelling and molecular-dynamic simulation methods, which demonstrated that EGFR and its homologue ErbB-2 could be possible in vivo ligands. The theory is further supported by the declining phosphorylation status of ErbB-2 after intratumoral administration of hPAP cDNA. However, hPAP has also been shown to be a universal protein phosphatase that hydrolyzes equally well the phosphotyrosine, -serine, and -threonine residues.
Within cells, the activity of hPAP is lower in prostate carcinomas than in normal prostates, and both hPAP mRNA and protein levels are decreased or absent in prostate carcinoma tissue. Similar effects can be observed in prostate cancer cell lines: the hPAP-expressing LNCaP cell line has a slower proliferation rate than the non-expressing PC-3 and DU-145 cells. Studies with transfected hPAP support the growth-suppressing effect. The present inventor has earlier demonstrated the binding of hPAP to the main high-density lipoprotein apolipoprotein A-1 (apoA-1). ApoA-1 is lipidated during its progress through intracellular vesicle traffic from the cell surface lipid raft into early endosomes, late endosomes, and finally back to the cell surface as a nascent HDL particle.
Animal models, such as transgenic or knockout animal models, may be used to investigate disorders related to certain genes. One such disorder is prostate cancer or tumor, which has been shown in the current invention to be associated with prostatic acid phosphatase in a specific way. In the art there are some known animal models which promote the formation of prostate tumor. For example review publication “Genetically defined mouse models that mimic natural aspects of human prostate cancer development” (Roy-Burman et al., Endocrine-Related Cancer (2004) 11:225-254) discloses several known mouse models for prostate cancer and exploitation thereof. This and all the other publications and other material disclosed herein are incorporated by reference.
The PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumor suppressor gene is one of the most frequently mutated/deleted genes in various human cancers. For example Wang et al. (Cancer Cell 4, 209-221) disclose a murine PTEN prostate cancer model.
WO 2004096153 describes prostate cancer therapeutics and speculates on animal models having knockout prostatic acid phosphatase gene. However, no actual animal models were disclosed.